Endometriosis is a disease in which endometrium or similar tissue grows at sites outside the uterus depending on the increased estrogen level. Although endometriosis is a benign disease, it causes pain such as menstrual pain and reduces fertility, and significantly reduces the quality of life (QOL) of women in their social and reproductive activities. Women with endometriosis have menstrual pain at an extremely high frequency and a symptom of pain such as lower abdominal pain not at their menstruation, low back pain, pain during or after sexual intercourse, pain during defecation and so on at a high frequency.
Many patients repeat exacerbation or recurrence of endometriosis before the menopause and thus endometriosis requires long-term treatment and management, unless they receive a radical surgical operation. As the first treatment for endometriosis, medication therapy is often selected. Medication therapy is generally classified into symptomatic and endocrine therapies. For symptomatic therapy, a medicine such as an analgesic agent is used in order to reduce endometriosis-associated pain. For endocrine therapy, in addition to reduction of pain, a low-dose formulated estrogen-progestin agent, dienogest, or gonadotropin releasing hormone (GnRH) agonist is used in order to suppress estrogen-dependent growth of endometrium.
Analgesic agents, however, have been considered not to be able to reduce endometriosis-associated pain in 10% to 30% of patients with endometriosis. Furthermore, in using a low-dose formulated estrogen-progestin agent, care should be taken for thrombosis, liver dysfunction and the others. Dienogest has been reported in a long-term study to have a 71.9% incidence of atypical genital bleeding as a side effect, which may result in severe anemia. GnRH agonists are, basically, not allowed to be administered for more than 6 months for a possible decrease of bone mineral density due to a decline in estrogen levels.
As described above, in medication therapy for treating endometriosis, continuous administration of medicament is difficult in many patients due to side effects specific for each of pharmaceutical agents. Accordingly, development of pharmaceutical agents that have fewer side effects and can be administered for a long period has been desired.
In the treatment of endometriosis, a concept called “estradiol therapeutic window” has been proposed as a threshold for blood estradiol (E2) level under which serious decrease of bone mineral density due to the effect of reducing estrogen levels does not occur while suppressing growth of the lesions of endometriosis (NPL 1). For example, NPL 1 describes that a therapeutic window would be an E2 level between 30 pg/mL and 50 pg/mL. Furthermore, it suggests that, at estradiol concentrations of lower than 20 pg/ml, the legions of endometriosis should atrophy but decrease of bone mineral density should be prominent.
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (hereinafter, referred to as Compound 1) represented by the following formula (I) is described in PTL 1. A choline salt of Compound 1 (hereinafter, referred to as Compound 2) is described in PTL 2. PTL 1 and PTL 2 describe that the Compound 2 and fused heterocyclic derivatives containing Compound 1 antagonize GnRH and can be used as pharmaceutical agents for preventing or treating sex hormone-dependent diseases such as prostatic hypertrophy, uterine fibrosis, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, and dysmenorrhea. PTL 1 and PTL 2 also describe that an oral dosage form can be manufactured in such a manner that the fused heterocyclic derivative or Compound 2 is administered at a dose ranging between 0.1 mg and 1000 mg.

PTL 1 and PTL 2 only describe general medical applications and general dosage of Compound 2 and fused heterocyclic derivatives containing Compound 1 based on GnRH antagonist activity. They do not specifically describe usages and dosages of Compounds 1 and 2 with which risk for decrease in bone mineral density due to their effect of reducing estrogen levels is reduced and their excellent therapeutic effects are exerted on endometriosis.